Revertant mosaicism (RM) is a very rare event by which pathogenic mutations are spontaneously corrected, giving rise to areas of normal tissue. However, in ichthyosis with confetti (IWC), a severe skin disorder due to dominant mutations affecting the tail domains of intermediate filament proteins keratin 10 (KRT10) or keratin 1 (KRT1), patients develop hundreds to thousands of revertant macules of normal skin, each arising from independent events of copy-neutral loss-of-heterozygosity (CN- LOH), likely due to homology-based mitotic recombination. This dramatic increase in the frequency of an otherwise rare event provides a unique opportunity to explore mechanisms of genetic reversion, which are currently poorly understood. In IWC, revertant patches grow in number and size over time, suggesting that revertant cells acquire a selective advantage over neighboring mutant cells. Notably, mutations in other domains of KRT10 or KRT1 lead to a distinct disorder known as epidermolytic ichthyosis (EI), which features an equally severe skin phenotype without clinical or genetic evidence of RM. This implicates a unique role of the tail domain of KRT10 and KRT1 in potentially regulating DNA recombination and repair. This project aims to determine whether the frequency of genetic reversion in IWC is a direct consequence of mutant KRT10 and KRT1 effects on homology-bases recombination, and whether cellular competition between revertant and mutant clones play a role in the formation and the expansion of revertant skin. To explore these possibilities, we have developed a conditional knock-in mouse model of IWC, which recapitulates clinical and histologic features of the disease, and, more importantly, shows evidence revertant mosaicism via LOH. We will employ this murine model alongside tools to interrogate rates of LOH, DNA damage and repair, and cellular competition, to explore the mechanisms underlying the frequent genetic self-correction seen in IWC skin. Elucidating the mechanisms of genetic reversion has potential to generate new therapeutic strategies against inherited and spontaneous genetic disorders, including methods to induce or alter the rate of reversion events.